Abstract:

There is provided a medicament comprising a combination of a
methylxanthine compound of formula I and a steroid of formula II and
their use as pharmaceuticals, in particular for the treatment of
inflammatory or obstructive airways diseases.

Claims:

1. A medicament comprising, separately or together(A) a methylxanthine
compound of formula I ##STR00006## or a salt thereof, whereX is hydrogen,
C1-C4-alkyl or --CO--NR3R4;R1 and R2 and
each independently C1-C4-alkyl;R3 is C1-C4-alkyl
and R4 is hydrogen or C1-C4-alkyl,or R3 and R4
together with the nitrogen atom to which they are attached is an
C1-C8-alkylene imino radical with 5 to 6 ring members or
morpholino; andR5 is hydrogen or C1-C4-alkyl; and(B) a
steroid of formula II ##STR00007## where T is a monovalent cyclic organic
group having from 3 to 15 atoms in the ring system,for simultaneous,
sequential or separate administration in the treatment of an inflammatory
or obstructive airways disease.

2. A medicament according to claim 1 which is a pharmaceutical composition
comprising a mixture of effective amounts of (A) and (B) optionally
together with at least one pharmaceutically acceptable carrier.

3. A medicament according to claim 1 wherein the methylxanthine compound
of formula I is theophylline.

4. A medicament according to claim 1, in which (B) is a steroid of formula
II where T is a heterocyclic aromatic group having a 5-membered
heterocyclic ring with one, two or three ring hetero atoms selected from
nitrogen, oxygen and sulfur, the heterocyclic ring being unsubstituted or
substituted by one or two substituents selected from halogen,
C1-C4-alkyl, halo-C1-C4-alkyl,
C1-C4-alkoxy, C1-C4-alkylthio, cyano or
hydroxy-C1-C4-alkyl, and the heterocyclic ring being optionally
fused to a benzene ring.

5. A medicament according to claim 1, in which (B) is a steroid of formula
II where T is a heterocyclic aromatic group having a 6-membered
heterocyclic ring with one or two ring nitrogen atoms, the heterocyclic
ring being unsubstituted or substituted by one or two substituents
selected from halogen, cyano, hydroxyl, C1-C4-acyloxy, amino,
C1-C4 alkylamino, di-(C1-C4-alkyl)amino,
C1-C4-alkyl, hydroxy-C1-C4-alkyl,
halo-C1-C4-alkyl C1-C4-alkoxy, or
C1-C4-alkylthio and the heterocyclic ring being optionally
fused to a benzene ring.

6. A medicament according to claim 1, in which (B) is a steroid of formula
II where T is 5-methyl-2-thienyl, N-methyl-2-pyrrolyl, cyclopropyl,
2-furyl, 3-methyl-2-furyl, 3-methyl-2-thienyl, 5-methyl-3-isoxazolyl,
3,5-dimethyl-2-thienyl, 2,5-dimethyl-3-furyl, 4-methyl-2-furyl,
4-(dimethylamino)phenyl, 4-methylphenyl, 4-ethyl-phenyl, 2-pyridyl,
4-pyrimidyl or 5-methyl-2-pyrazinyl or the indicated 16-methyl group has
the beta conformation and R is cyclopropyl.

7. A medicament according to claim 4, in which (B) is
3-methyl-thiophene-2-carboxylic acid
(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbon-
yl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
-cyclopenta-[a]phenanthren-17-yl ester.

8. A medicament according to claim 1, in which (A) is theophylline or a
salt thereof and (B) is 3-methyl-thiophene-2-carboxylic acid
(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbon-
yl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
-cyclopenta-[a]phenanthren-17-yl ester.

9. A medicament, comprising, separately or together(A) a methylxanthine
compound of formula I ##STR00008## or a salt thereof, whereX is hydrogen,
C1-C4-alkyl or --CO--NR3R4;R1 and R2 and
each independently C1-C4-alkyl,R3 is C1-C4-alkyl
and R4 is hydrogen or C1-C4-alkyl,or R3 and R4
together with the nitrogen atom to which they are attached is an
C1-C8-alkylene imino radical with 5 to 6 ring members or
morpholino; andR5 is hydrogen or C1-C4-alkyl; and(B) a
steroid of formula II ##STR00009## where T is a monovalent cyclic organic
group having from 3 to 15 atoms in the ring system,for simultaneous,
sequential or separate administration in the treatment of an inflammatory
or obstructive airways disease, which is in inhalable form and is(i) an
aerosol comprising a mixture of (A) and (B) in solution or dispersion in
a propellant;(ii) a combination of an aerosol containing (A) in solution
or dispersion in a propellant, with an aerosol containing (B) in solution
or dispersion in a propellant;(iii) a nebulizable composition comprising
a dispersion of (A) and (B) in an aqueous, organic or aqueous/organic
medium; or(iv) a combination of a dispersion of (A) in an aqueous,
organic or aqueous/organic medium with a dispersion of (B) in an aqueous,
organic or aqueous/organic medium.

10. A medicament according to claim 1, in which (A) and (B) are present in
inhalable form as a dry powder comprising finely divided (A) and (B)
optionally together with at least one particulate pharmaceutically
acceptable carrier.

11. A medicament according to claim 1, in which (A) and (B) have an
average particle diameter of up to 10 μm.

12. A medicament comprising, separately or together(A) a methylxanthine
compound of formula I ##STR00010## or a salt thereof, whereX is hydrogen,
C1-C4-alkyl or --CO--NR3R4;R1 and R2 and
each independently C1-C4-alkyl,R3 is C1-C4-alkyl
and R4 is hydrogen or C1-C4-alkyl,or R3 and R4
together with the nitrogen atom to which they are attached is an
C1-C8-alkylene imino radical with 5 to 6 ring members or
morpholino; andR5 is hydrogen or C1-C4-alkyl; and(B) a
steroid of formula II ##STR00011## where T is a monovalent cyclic organic
group having from 3 to 15 atoms in the ring system,for simultaneous,
sequential or separate administration in the treatment of an inflammatory
or obstructive airways disease, which is a dry powder in a capsule, the
capsule containing a unit dose of (A), a unit dose of (B) and a
pharmaceutically acceptable carrier in an amount to bring the total
weight of dry powder per capsule to between 5 mg and 50 mg; or an aerosol
comprising (A) and (B) in a propellant, optionally together with a
surfactant and/or a bulking agent and/or a co-solvent suitable for
administration from a metered dose inhaler adapted to deliver an amount
of aerosol containing a unit dose of (A) and a unit dose of (B), or a
known fraction of a unit dose of (A) and a known fraction of a unit dose
of (B), per actuation.

13. A medicament according to claim 1, in which the weight ratio of (A) to
(B) is from 2:1 to 1:2000.

14-17. (canceled)

18. A medicament according to claim 9 which is a pharmaceutical
composition comprising a mixture of effective amounts of (A) and (B)
optionally together with at least one pharmaceutically acceptable
carrier.

19. A medicament according to claim 9 wherein the (A) formula I is
theophylline.

20. A medicament according to claim 9, in which (B) is a steroid of
formula II where T is a heterocyclic aromatic group having a 5-membered
heterocyclic ring with one, two or three ring hetero atoms selected from
nitrogen, oxygen and sulfur, the heterocyclic ring being unsubstituted or
substituted by one or two substituents selected from halogen,
C1-C4-alkyl, halo-C1-C4-alkyl,
C1-C4-alkoxy, C1-C4-alkylthio, cyano or
hydroxy-C1-C4-alkyl, and the heterocyclic ring being optionally
fused to a benzene ring.

21. A medicament according to claim 9, in which (B) is a steroid of
formula II where T is a heterocyclic aromatic group having a 6-membered
heterocyclic ring with one or two ring nitrogen atoms, the heterocyclic
ring being unsubstituted or substituted by one or two substituents
selected from halogen, cyano, hydroxyl, C1-C4-acyloxy, amino,
C1-C4 alkylamino, di-(C1-C4-alkyl)amino,
C1-C4-alkyl, hydroxy-C1-C4-alkyl,
halo-C1-C4-alkyl C1-C4-alkoxy, or
C1-C4-alkylthio and the heterocyclic ring being optionally
fused to a benzene ring.

22. A medicament according to claim 9, in which (B) is a steroid of
formula II where T is 5-methyl-2-thienyl, N-methyl-2-pyrrolyl,
cyclopropyl, 2-furyl, 3-methyl-2-furyl, 3-methyl-2-thienyl,
5-methyl-3-isoxazolyl, 3,5-dimethyl-2-thienyl, 2,5-dimethyl-3-furyl,
4-methyl-2-furyl, 4-(dimethylamino)phenyl, 4-methylphenyl,
4-ethyl-phenyl, 2-pyridyl, 4-pyrimidyl or 5-methyl-2-pyrazinyl or the
indicated 16-methyl group has the beta conformation and R is cyclopropyl.

23. A medicament according to claim 20, in which (B) is
3-methyl-thiophene-2-carboxylic acid
(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbon-
yl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
-cyclopenta-[a]phenanthren-17-yl ester.

24. A medicament according to claim 9, in which (A) is theophylline or a
salt thereof and (B) is 3-methyl-thiophene-2-carboxylic acid
(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbon-
yl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
-cyclopenta-[a]phenanthren-17-yl ester.

25. A medicament according to claim 9, in which (A) and (B) are present in
inhalable form as a dry powder comprising finely divided (A) and (B)
optionally together with at least one particulate pharmaceutically
acceptable carrier.

26. A medicament according to claim 9, in which (A) and (B) have an
average particle diameter of up to 10 μm.

27. A medicament according to 9, in which the weight ratio of (A) to (B)
is from 2:1 to 1:2000.

28. A medicament according to claim 12 which is a pharmaceutical
composition comprising a mixture of effective amounts of (A) and (B)
optionally together with at least one pharmaceutically acceptable
carrier.

29. A medicament according to claim 12 wherein the (A) formula I is
theophylline.

30. A medicament according to claim 12, in which (B) is a steroid of
formula II where T is a heterocyclic aromatic group having a 5-membered
heterocyclic ring with one, two or three ring hetero atoms selected from
nitrogen, oxygen and sulfur, the heterocyclic ring being unsubstituted or
substituted by one or two substituents selected from halogen,
C1-C4-alkyl, halo-C1-C4-alkyl,
C1-C4-alkoxy, C1-C4-alkylthio, cyano or
hydroxy-C1-C4-alkyl, and the heterocyclic ring being optionally
fused to a benzene ring.

31. A medicament according to claim 12, in which (B) is a steroid of
formula II where T is a heterocyclic aromatic group having a 6-membered
heterocyclic ring with one or two ring nitrogen atoms, the heterocyclic
ring being unsubstituted or substituted by one or two substituents
selected from halogen, cyano, hydroxyl, C1-C4-acyloxy, amino,
C1-C4 alkylamino, di-(C1-C4-alkyl)amino,
C1-C4-alkyl, hydroxy-C1-C4-alkyl,
halo-C1-C4-alkyl C1-C4-alkoxy, or
C1-C4-alkylthio and the heterocyclic ring being optionally
fused to a benzene ring.

32. A medicament according to claim 12, in which (B) is a steroid of
formula II where T is 5-methyl-2-thienyl, N-methyl-2-pyrrolyl,
cyclopropyl, 2-furyl, 3-methyl-2-furyl, 3-methyl-2-thienyl,
5-methyl-3-isoxazolyl, 3,5-dimethyl-2-thienyl, 2,5-dimethyl-3-furyl,
4-methyl-2-furyl, 4-(dimethylamino)phenyl, 4-methylphenyl,
4-ethyl-phenyl, 2-pyridyl, 4-pyrimidyl or 5-methyl-2-pyrazinyl or the
indicated 16-methyl group has the beta conformation and R is cyclopropyl.

33. A medicament according to claim 30, in which (B) is
3-methyl-thiophene-2-carboxylic acid
(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbon-
yl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
-cyclopenta-[a]phenanthren-17-yl ester.

34. A medicament according to claim 12, in which (A) is theophylline or a
salt thereof and (B) is 3-methyl-thiophene-2-carboxylic acid
(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbon-
yl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
-cyclopenta-[a]phenanthren-17-yl ester.

35. A medicament according to claim 12, in which (A) and (B) are present
in inhalable form as a dry powder comprising finely divided (A) and (B)
optionally together with at least one particulate pharmaceutically
acceptable carrier.

36. A medicament according to claim 12, in which (A) and (B) have an
average particle diameter of up to 10 μm.

37. A medicament according to 12, in which the weight ratio of (A) to (B)
is from 2:1 to 1:2000.

38. A method of treating an inflammatory or obstructive airway disease in
a subject in need of such treatment, which comprises administering to
said subject a medicament comprising, separately or together (A) a
methylxanthine compound of formula I as defined in claim 1 and (B) a
steroid of formula II as defined in claim 1, for combination therapy by
simultaneous, sequential or separate administration.

39. A method of treating an inflammatory or obstructive airway disease in
a subject in need of such treatment, which comprises administering to
said subject a medicament comprising, separately or together (A) a
methylxanthine compound of formula I as defined in claim 9 and (B) a
steroid of formula II as defined in claim 9, for combination therapy by
simultaneous, sequential or separate administration.

40. A method of treating an inflammatory or obstructive airway disease in
a subject in need of such treatment, which comprises administering to
said subject a medicament comprising, separately or together (A) a
methylxanthine compound of formula I as defined in claim 12 and (B) a
steroid of formula II as defined in claim 12, for combination therapy by
simultaneous, sequential or separate administration.

41. A pharmaceutical kit comprising (A) a methylxanthine compound of
formula I as defined in claim 1 and (B) a steroid of formula II as
defined in claim 1, in separate unit dosage forms, said forms being
suitable for administration of (A) and (B) in effective amounts, together
with one or more inhalation devices for administration of (A) and (B).

42. A pharmaceutical kit comprising (A) a methylxanthine compound of
formula I as defined in claim 9 and (B) a steroid of formula II as
defined in claim 9, in separate unit dosage forms, said forms being
suitable for administration of (A) and (B) in effective amounts, together
with one or more inhalation devices for administration of (A) and (B).

43. A pharmaceutical kit comprising (A) a methylxanthine compound of
formula I as defined in claim 12 and (B) a steroid of formula II as
defined in claim 12, in separate unit dosage forms, said forms being
suitable for administration of (A) and (B) in effective amounts, together
with one or more inhalation devices for administration of (A) and (B).

Description:

[0001]This invention relates to a combination of steroids and
methylxanthine compounds and their use as pharmaceuticals, in particular
for the treatment of inflammatory or obstructive airways diseases.

[0002]In a first aspect, the present invention provides a medicament
comprising, separately or together (A) a methylxanthine compound of
formula I

##STR00001##

or a salt thereof, whereX is hydrogen, C1-C4-alkyl or
--CO--NR3R4;R1 and R2 and each independently
C1-C4-alkyl;R3 is C1-C4-alkyl and R4 is
hydrogen or C1-C4-alkyl,or R3 and R4 together with
the nitrogen atom to which they are attached is an
C1-C8-alkylene imino radical with 5 to 6 ring members or
morpholino; andR5 is hydrogen or C1-C4-alkyl; and(B) a
steroid of formula II

##STR00002##

where T is a monovalent cyclic organic group having from 3 to 15 atoms in
the ring system, for simultaneous, sequential or separate administration
in the treatment of an inflammatory or obstructive airways disease.

[0003]Methylxanthine compounds of formula I include theophylline and
pharmacologically equivalent compounds and salts, such as aminophylline
and oxtriphylline, as well as caffeine, theobromine, furaphylline,
7-propyl-theophylline-dopamine and enprofylline.

[0004]Compounds of formula II are anti-inflammatory corticosteroids that
are disclosed in international patent application WO 02/00679, the
contents of which is incorporated herein by reference.

[0005]It has now surprisingly been found that a significant unexpected
therapeutic benefit, particularly a synergistic therapeutic benefit, in
the treatment of inflammatory or obstructive airways diseases can be
obtained by combination therapy using a methylxanthine compound of
formula I and a steroid of formula II. For instance, it is possible using
this combination therapy to reduce the dosages of one or both of the two
active ingredients required for a given therapeutic effect considerably
compared with those required using treatment with the active ingredients
alone, thereby minimising possibly undesirable side effects. In
particular, it has been found that these combinations induce an
anti-inflammatory activity which is significantly greater than that
induced by a methylxanthine compound of formula I or a steroid of formula
II alone. The amount of a steroid of formula II in particular needed for
a given anti-inflammatory effect may be significantly reduced when used
in admixture with a methylxanthine compound of formula I, thereby
reducing the risk of undesirable side effects from the repeated exposure
to the steroid involved in the treatment of inflammatory or obstructive
airways diseases.

[0006]Furthermore, using the combination therapy of the invention,
particularly using compositions containing theophylline and a steroid of
formula II, medicaments which have a rapid onset of action and a long
duration of action may be prepared. Moreover, using such combination
therapy, medicaments which result in a significant improvement in lung
function may be prepared. Using the combination therapy of the invention,
medicaments which provide improved control of obstructive or inflammatory
airways diseases, or a reduction in exacerbations of such diseases, may
be prepared. Using compositions of the invention, medicaments which can
be used on demand in rescue treatment of obstructive or inflammatory
airways diseases, or which reduce or eliminate the need for treatment
with short-acting rescue medicaments such as salbutamol or terbutaline,
may be prepared; thus medicaments based on compositions of the invention
facilitate the treatment of an obstructive or inflammatory airways
disease with a single medicament.

[0007]Accordingly, in a second aspect, the present invention provides a
pharmaceutical composition comprising a mixture of effective amounts of
(A) a methylxanthine compound of formula I and (B) a steroid of formula
II, optionally together with at least one pharmaceutically acceptable
carrier.

[0008]In a third aspect, the present invention provides a method of
treating an inflammatory or obstructive airways disease which comprises
administering to a subject in need of such treatment effective amounts of
(A) a methylxanthine compound of formula I and (B) a steroid of formula
II.

[0009]The invention further provides the use of (A) a methylxanthine
compound of formula I and (B) a steroid of formula II in the preparation
of a medicament for combination therapy by simultaneous, sequential or
separate administration of (A) and (B) in the treatment of an
inflammatory or obstructive airways disease.

[0018]In one aspect, the present invention provides a medicament
comprising, separately or together (A) a methylxanthine compound of
formula I and (B) a steroid of formula II, for simultaneous, sequential
or separate administration in the treatment of an inflammatory or
obstructive airways disease.

[0019]The methylxanthine compound of formula I is preferably theophylline
or a pharmacologically equivalent compound or salt thereof.

[0020]Theophylline is a naturally occurring alkaloid found in tea. It is
available as a number of different salts, the most common of which are
aminophylline (the ethylenediamine) and choline theophyllinate. It has
the structure shown below

[0021]Theophylline works as a bronchodilator by the relaxation of
bronchial smooth muscle. Several mechanisms have been proposed which
include the inhibition of phosphodiesterase to increase intracellular
cAMP levels. Theophylline is an antagonist of adenosine at
pharmacological doses. It has also been shown to have some
anti-inflammatory activity, inhibiting the activity of CD4 lymphocytes in
vitro and mediator release from mast cells, and can inhibit
bronchoconstriction produced by exercise and challenge testing.

[0022]Theophylline has more recently been shown to activate histone
deacetylase (HDAC). Acetylation of histone proteins is associated with
activation of gene function, and it is believed that proinflammatory
transcription factors which activate inflammatory genes also cause an
increase in histone actetyltransferase activity. By increasing HDAC
activity and so deacetylating histone proteins, theophylline is believed
to suppress the expression of inflammatory genes (see Barnes, (2003) Am J
Respir Crit Care Med 167:813-818).

[0023]Steroids of formula II are disclosed, together with procedures for
their preparation in international patent application WO 02/00679, the
contents of which is incorporated herein by reference. These compounds
exhibit surprisingly low systemic side effects at therapeutically
effective doses and have a long duration of action, with a potential for
once-a-day administration.

[0024]In one embodiment, T is a heterocyclic aromatic group having a
5-membered heterocyclic ring with one, two or three ring hetero atoms
selected from nitrogen, oxygen and sulfur, the heterocyclic ring being
unsubstituted or substituted by one or two substituents selected from
halogen, C1-C4-alkyl, halo-C1-C4-alkyl,
C1-C4-alkoxy, C1-C4-alkyl-thio, cyano or
hydroxy-C1-C4-alkyl and the heterocyclic ring being optionally
fused to a benzene ring. Preferred such heterocyclic aromatic groups
include those in which the heterocyclic ring has one nitrogen, oxygen or
sulfur atom in the ring or one oxygen and one or two nitrogen atoms in
the ring, or one sulfur and one or two nitrogen atoms in the ring,
especially a pyrrole, furan, thiophene, oxazole, isoxazole, imidazole,
pyrazole, furazan, thiazole or thiadiazole ring. Especially preferred
heterocyclic aromatic groups are pyrrolyl, furyl and thienyl groups
optionally substituted by one or two substituents selected from halogen
(particularly chlorine or bromine), C1-C4-alkyl (particularly
methyl or ethyl), halo-C1-C4-alkyl (particularly
trifluoro-methyl), C1-C4-alkoxy (particularly methoxy),
C1-C4-alkylthio (particularly methylthio), cyano or
hydroxy-C1-C4-alkyl (particularly hydroxymethyl); isoxazolyl,
imidazolyl, pyrazolyl, thiazolyl or thiadiazolyl groups optionally
substituted by one or two C1-C4-alkyl groups; and benzofuryl,
benzothienyl and benzofurazanyl groups.

[0025]In another embodiment, T is a heterocyclic aromatic group having a
6-membered heterocyclic ring with one, two or three ring heteroatoms,
preferably nitrogen, the heterocyclic ring being unsubstituted or
substituted by one or more, preferably one, two or three, substituents
selected from halogen, cyano, hydroxyl, C1-C4-acyloxy, amino,
C1-C4-alkyl-amino, di-(C1-C4-alkyl)amino,
C1-C4-alkyl, hydroxy-C1-C4-alkyl,
halo-C1-C4-alkyl, C1-C4-alkoxy, or
C1-C4-alkylthio, and the heterocyclic ring being optionally
fused to a benzene ring. Preferred such heterocyclic aromatic groups
include those in which the heterocyclic group has one or two nitrogen
atoms in the ring, especially a pyridine, pyrimidine, pyrazine or
pyridazine ring. Especially preferred heterocyclic aromatic groups are
pyridyl, pyrimidinyl and pyrazinyl groups, optionally substituted by one
or two substituents selected from halogen (particularly chlorine) or
C1-C4-alkyl (especially methyl or n-butyl).

[0026]In steroids of formula II, the indicated methyl group in the 16
position of the cortico-steroid ring system may be in the alpha or beta
conformation. 16-α-methyl compounds are preferred.

[0027]Preferred steroids of formula II are those where the indicated
16-methyl group has the alpha conformation and T is 5-methyl-2-thienyl,
N-methyl-2-pyrrolyl, cyclopropyl, 2-furyl, 3-methyl-2-furyl,
3-methyl-2-thienyl, 5-methyl-3-isoxazolyl, 3,5-dimethyl-2-thienyl,
2,5-dimethyl-3-furyl, 4-methyl-2-furyl, 4-(dimethylamino)phenyl,
4-methylphenyl, 4-ethylphenyl, 2-pyridyl, 4-pyrimidyl or
5-methyl-2-pyrazinyl or the indicated 16-methyl group has the beta
conformation and R is cyclopropyl.

[0030]Administration of the medicament or pharmaceutical composition as
hereinbefore described, i.e. with (A) and (B) in admixture or separate,
is preferably by inhalation, i.e. (A) and (B) or the mixture thereof are
in inhalable form.

[0031]The inhalable form of the medicament may be, for example, an
atomizable composition such as an aerosol comprising the active
ingredients, i.e. (A) and (B) separately or in admixture, in solution or
dispersion in a propellant, or a nebulisable composition comprising a
solution or dispersion of the active ingredient in an aqueous, organic or
aqueous/organic medium. For example, the inhalable form of the medicament
may be an aerosol comprising a mixture of (A) and (B) in solution or
dispersion in a propellant. In another example, the inhalable form is a
nebulizable composition comprising a dispersion of (A) and (B) in an
aqueous, organic or aqueous/organic medium.

[0032]An aerosol composition suitable for use as the inhalable form of the
medicament may comprise the active ingredient in solution or dispersion
in a propellant, which may be chosen from any of the propellants known in
the art. Suitable such propellants include hydrocarbons such as
n-propane, n-butane or isobutane or mixtures of two or more such
hydrocarbons, and halogen-substituted hydrocarbons, for example chlorine
and/or fluorine-substituted methanes, ethanes, propanes, butanes,
cyclopropanes or cyclobutanes, such as dichlorodifluoromethane (CFC-12),
trichlorofluoromethane (CFC-11), 1,2-dichloro-1,1,2,2-tetrafluoroethane
(CFC-114) or, particularly, 1,1,1,2-tetrafluoroethane (HFA-134a),
1,1,1,2,3,3,3-heptafluoropropane (HFA-227), difluorochloromethane
(HCFC-22) or mixtures of two or more such halogen-substituted
hydrocarbons.

[0033]Where the active ingredient is present in suspension in the
propellant, i.e. where it is present in particulate form dispersed in the
propellant, the aerosol composition may also contain a lubricant and a
surfactant, which may be chosen from those lubricants and surfactants
known in the art. Other suitable aerosol compositions include
surfactant-free or substantially surfactant-free aerosol compositions.
The aerosol composition may contain up to about 5% by weight, for example
0.0001 to 5%, 0.001 to 5%, 0.001 to 3%, 0.001 to 2%, 0.001 to 1%, 0.001
to 0.1%, or 0.001 to 0.01%, but preferably 0.01 to 0.5% by weight of the
active ingredient, based on the weight of the propellant. Where present,
the lubricant and surfactant may be in an amount up to 5% and 0.5%
respectively by weight of the aerosol composition. The aerosol
composition may also contain a co-solvent such as ethanol in an amount up
to 30% by weight of the composition, particularly for administration from
a pressurised metered dose inhalation device. The aerosol composition may
further contain a bulking agent, for example a sugar such as lactose,
sucrose, dextrose, mannitol or sorbitol, in an amount, for example, of up
to 20%, usually 0.001 to 1%, by weight of the composition.

[0034]In another embodiment of the invention, the inhalable form of the
medicament is a dry powder, i.e. (A) and (B) are present in a dry powder
comprising finely divided (A) and (B) optionally together with at least
one particulate pharmaceutically acceptable carrier, which may be one or
more materials known as pharmaceutically acceptable carriers, preferably
chosen from materials known as carriers in dry powder inhalation
compositions, for example saccharides, including monosaccharides,
disaccharides, polysaccharides and sugar alcohols such as arabinose,
glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose,
starches, dextran, mannitol or sorbitol. An especially preferred carrier
is lactose, for example lactose monohydrate or anhydrous lactose. The dry
powder may be contained as unit doses in capsules of, for example,
gelatin or plastic, or in blisters (e.g. of aluminium or plastic), for
use in a dry powder inhalation device, which may be a single dose or
multiple dose device, preferably in dosage units of (A) and/or (B)
together with the carrier in amounts to bring the total weight of powder
per capsule to from 5 mg to 50 mg. Alternatively, the dry powder may be
contained in a reservoir in a multi-dose dry powder inhalation device
adapted to deliver, for example, 3-25 mg of dry powder per actuation.

[0035]In the finely divided particulate form of the medicament, and in the
aerosol composition where at least one of the active ingredients are
present in particulate form, the active ingredient may have an average
particle diameter of up to about 10 μm, for example 0.1 to 5 μm,
preferably 1 to 5 μm. The particulate carrier, where present,
generally has a maximum particle diameter up to 500 μm, preferably up
to 400 μm, and conveniently has a mean particle diameter of 40 to 300
μm, e.g. 50 to 250 μm. The particle size of the active ingredient,
and that of a particulate carrier where present in dry powder
compositions, can be reduced to the desired level by conventional
methods, for example by grinding in an air-jet mill, ball mill or
vibrator mill, sieving, microprecipitation, spray-drying, lyophilisation
or controlled crystallisation from conventional solvents or from
supercritical media.

[0036]The inhalable medicament may be administered using an inhalation
device suitable for the inhalable form, such devices being well known in
the art. Accordingly, the invention also provides a pharmaceutical
product comprising a medicament or pharmaceutical composition as
hereinbefore described in inhalable form as hereinbefore described in
association with one or more inhalation devices. In a further aspect, the
invention provides an inhalation device, or a pack of two or more
inhalation devices, containing a medicament or pharmaceutical composition
as hereinbefore described in inhalable form as hereinbefore described.

[0037]Where the inhalable form of the active ingredient is an aerosol
composition, the inhalation device may be an aerosol vial provided with a
valve adapted to deliver a metered dose, such as 10 to 100 μl, e.g. 25
to 50 μl, of the composition, i.e. a device known as a metered dose
inhaler. Suitable such aerosol vials and procedures for containing within
them aerosol compositions under pressure are well known to those skilled
in the art of inhalation therapy. For example, an aerosol composition may
be administered from a coated can, for example as described in
EP-A-0642992.

[0038]Where the inhalable form of the active ingredient is a nebulizable
aqueous, organic or aqueous/organic dispersion, the inhalation device may
be a known nebulizer, for example a conventional pneumatic nebulizer such
as an airjet nebulizer, or an ultrasonic nebulizer, which may contain,
for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or
a hand-held nebulizer, sometimes referred to as a soft mist or soft spray
inhaler, for example an electronically controlled device such as an AERx
(Aradigm, US) or Aerodose (Aerogen), or a mechanical device such as a
RESPIMAT (Boehringer Ingelheim) nebulizer which allows much smaller
nebulised volumes, e.g. 10 to 100 μl, than conventional nebulisers.

[0039]Where the inhalable form of the active ingredient is the finely
divided particulate form, the inhalation device may be, for example, a
dry powder inhalation device adapted to deliver dry powder from a capsule
or blister containing a dry powder comprising a dosage unit of (A) and/or
(B) or a multidose dry powder inhalation (MDDPI) device adapted to
deliver, for example, 3-25 mg of dry powder comprising a dosage unit of
(A) and/or (B) per actuation. The dry powder composition preferably
contains a diluent or carrier, such as lactose, and a compound that helps
to protect against product performance deterioration due to moisture e.g.
magnesium stearate, typically 0.05-2.0%. Suitable such dry powder
inhalation devices are well known. For example, a suitable device for
delivery of dry powder in encapsulated form is that described in U.S.
Pat. No. 3,991,761, while suitable MDDPI devices include those described
in WO 97/20589 and WO 97/30743.

[0040]The medicament of the invention is preferably a pharmaceutical
composition comprising a mixture of (A) a methylxanthine compound of
formula I and (B) a steroid of formula II, preferably together with at
least one pharmaceutically acceptable carrier as hereinbefore described.

[0041]The weight ratio of the methylxanthine compound of formula I to the
steroid of formula II may be, in general, from 2:1 to 1:2000, for example
from 1:1 to 1:1000, from 1:2 to 1:100, or from 1:5 to 1:50. More usually,
this ratio is from 1:10 to 1:25, for example from 1:15 to 1:25. The two
drugs may be administered separately in the same ratio. Specific examples
of this ratio, to the nearest whole number, include 1:10, 1:11, 1:12,
1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24
and 1:25.

[0042]A suitable daily dose of (A) the methylxanthine compound of formula
I, particularly theophylline, for inhalation may be from 10 μg to 2000
μg, preferably from 20 to 1000 μg, and especially from 20 to 800
μg, e.g. from 30 to 500 μg.

[0043]A suitable daily dose of (B) a steroid of formula I for inhalation
may be from 50 to 2000 μg, for example from 100 to 2000 μg, from
100 to 1600 μg, from 100 to 1000 μg, or from 100 to 800 μg,
preferably from 200 to 500 μg, for instance from 200 to 400 μg.

[0044]A suitable unit dose of (A) the methylxanthine compound of formula
I, particularly theophylline, for inhalation may be from 10 μg to 2000
μg, preferably from 20 to 1000 μg, and especially from 20 to 800
μg, e.g. from 30 to 500 μg.

[0045]A suitable unit dose of (B) a steroid of formula II for inhalation
may be from 50 to 2000 μg, for example from 100 to 2000 μg, from
100 to 1600 μg, from 100 to 1000 μg, or from 100 to 800 μg,
preferably from 200 to 500 μg, for instance from 200 to 400 μg.

[0046]These unit doses may be administered once or twice daily in
accordance with the daily doses mentioned hereinbefore. A single dose is
preferred as this is convenient for the patient and encourages
compliance. The precise doses of (A) and (B) used will of course depend
on the condition to be treated, the patient and the efficiency of the
inhalation device.

[0047]In one preferred embodiment of the invention, the medicament of the
invention is a pharmaceutical composition which is a dry powder in a
capsule containing unit doses of (A) a methylxanthine compound of formula
I as hereinbefore defined and (B) a steroid of formula II as hereinbefore
defined, for example for inhalation from a single capsule inhaler, the
capsule suitably containing a unit dose of (A) a methylxanthine compound
of formula I and a unit dose of (B) a steroid of formula II, together
with a pharmaceutically acceptable carrier as hereinbefore described in
an amount to bring the total weight of dry powder per capsule to between
5 mg and 50 mg, for example 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35
mg, 40 mg, 45 mg or 50 mg.

[0048]In another preferred embodiment of the invention, the medicament of
the invention is a pharmaceutical composition which is a dry powder for
administration from a reservoir of a multi-dose dry powder inhaler
adapted to deliver, for example, 3 mg to 25 mg of powder containing a
unit dose of (A) a methylxanthine compound of formula I and (B) a steroid
of formula II per actuation.

[0049]In a further preferred embodiment of the invention, the medicament
of the invention is a pharmaceutical composition which is an aerosol
comprising (A) a methylxanthine compound of formula I as hereinbefore
described and (B) a steroid of formula II as hereinbefore described in a
propellant, optionally together with a surfactant and/or a bulking agent
and/or a co-solvent such as ethanol as hereinbefore described, for
administration from a metered dose inhaler adapted to deliver an amount
of aerosol containing a unit dose of (A) a methylxanthine compound of
formula I and a unit dose of (B) a steroid of formula II, or a known
fraction of a unit dose of (A) a methylxanthine compound of formula I and
a known fraction of a unit dose of (B) a steroid of formula II per
actuation. Thus if, for example, the inhaler delivers half of the unit
doses of (A) a methylxanthine compound of formula I and (B) a steroid of
formula II per actuation, the unit doses can be administered by two
actuations of the inhaler.

[0050]In accordance with the above, the invention also provides a
pharmaceutical kit comprising (A) a methylxanthine compound of formula I
and (B) a steroid of formula II in separate unit dosage forms, said forms
being suitable for administration of (A) a methylxanthine compound of
formula I and (B) a steroid of formula II in effective amounts. Such a
kit suitably further comprises one or two inhalation devices for
administration of (A) a methylxanthine compound of formula I and (B) a
steroid of formula II. For example, the kit may comprise one or more dry
powder inhalation devices adapted to deliver dry powder from a capsule,
together with capsules containing a dry powder comprising a dosage unit
of (A) a methylxanthine compound of formula I and capsules containing a
dry powder comprising a dosage unit of (B) a steroid of formula II. In
another example, the kit may comprise a multi-dose dry powder inhalation
device containing in the reservoir thereof a dry powder comprising (A) a
methylxanthine compound of formula I and a multi-dose dry powder
inhalation device containing in the reservoir thereof a dry powder
comprising (B) a steroid of formula II. In a further example, the kit may
comprise a metered dose inhaler containing an aerosol comprising (A) a
methylxanthine compound of formula I in a propellant and a metered dose
inhaler containing an aerosol comprising (B) a steroid of formula II in a
propellant.

[0051]Medicaments of the invention are advantageous in the treatment of
inflammatory or obstructive airways disease, exhibiting highly effective
bronchodilatory and anti-inflammatory properties. For instance, it is
possible using the combination therapy of the invention to reduce the
dosages of corticosteroid required for a given therapeutic effect
compared with those required using treatment with a corticosteroid alone,
thereby minimising possibly undesirable side effects. In particular,
these combinations, particularly where (A) a methylxanthine compound of
formula I and (B) a steroid of formula II are in the same composition,
facilitate achievement of a high anti-inflammatory effect, such that the
amount of corticosteroid needed for a given anti-inflammatory effect may
be reduced when used in admixture with (A) a methylxanthine compound of
formula I and (B) a steroid of formula II, thereby reducing the risk of
undesirable side effects from the repeated exposure to the steroid
involved in the treatment of inflammatory or obstructive airways
diseases. Furthermore, using the combinations of the invention,
medicaments which have a rapid onset of action and a long duration of
action may be prepared. Moreover, using such combination therapy,
medicaments which result in a significant improvement in lung function
may be prepared. In another aspect, using the combination therapy of the
invention, medicaments which provide effective control of obstructive or
inflammatory airways diseases, or a reduction in exacerbations of such
diseases, may be prepared. In a further aspect, using compositions of the
invention containing (A) a methylxanthine compound of formula I and (B) a
steroid of formula II, medicaments which reduce or eliminate the need for
treatment with short-acting rescue medicaments such as salbutamol or
terbutaline, may be prepared; thus compositions of the invention
facilitate the treatment of an obstructive or inflammatory airways
disease with a single medicament.

[0052]Treatment of inflammatory or obstructive airways diseases in
accordance with the invention may be symptomatic or prophylactic
treatment. Inflammatory or obstructive airways diseases to which the
present invention is applicable include asthma of whatever type or
genesis including both intrinsic (non-allergic) asthma and extrinsic
(allergic) asthma, mild asthma, moderate asthma, severe asthma,
bronchitic asthma, exercise-induced asthma, occupational asthma and
asthma induced following bacterial infection. Treatment of asthma is also
to be understood as embracing treatment of subjects, e.g. of less than 4
or 5 years of age, exhibiting wheezing symptoms and diagnosed or
diagnosable as "wheezy infants", an established patient category of major
medical concern and now often identified as incipient or early-phase
asthmatics. (For convenience this particular asthmatic condition is
referred to as "wheezy-infant syndrome".)

[0053]Prophylactic efficacy in the treatment of asthma will be evidenced
by reduced frequency or severity of symptomatic attack, e.g. of acute
asthmatic or bronchoconstrictor attack, improvement in lung function or
improved airways hyperreactivity. It may further be evidenced by reduced
requirement for other, symptomatic therapy, i.e. therapy for or intended
to restrict or abort symptomatic attack when it occurs, for example
anti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylactic
benefit in asthma may in particular be apparent in subjects prone to
"morning dipping". "Morning dipping" is a recognised asthmatic syndrome,
common to a substantial percentage of asthmatics and characterised by
asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time
normally substantially distant form any previously administered
symptomatic asthma therapy. Other inflammatory or obstructive airways
diseases and conditions to which the present invention is applicable
include acute lung injury (ALI), adult or acute respiratory distress
syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease
(COPD, COAD or COLD), including chronic bronchitis and emphysema,
bronchiectasis and exacerbation of airways hyperreactivity consequent to
other drug therapy, in particular other inhaled drug therapy. Further
inflammatory or obstructive airways diseases to which the present
invention is applicable include pneumoconiosis (an inflammatory, commonly
occupational, disease of the lungs, frequently accompanied by airways
obstruction, whether chronic or acute, and occasioned by repeated
inhalation of dusts) of whatever type or genesis, including, for example,
aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis,
silicosis, tobacosis and byssinosis, cystic fibrosis and pulmonary
hypertension, including primary pulmonary hypertension.

[0054]The medicament of the present invention may additionally contain one
or more co-therapeutic agents such as anti-inflammatory, bronchodilatory,
antihistamine, decongestant or anti-tussive drug substances, particularly
in the treatment of obstructive or inflammatory airways diseases such as
those mentioned hereinbefore, for example as potentiators of therapeutic
activity of such drugs or as a means of reducing required dosaging or
potential side effects of such drugs.

[0066]The invention is illustrated by the following Examples, in which
parts are by weight unless stated otherwise. In the examples Compound B
is 3-methyl-thiophene-2-carboxylic acid
(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxy-carbo-
nyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3-
H-cyclopenta-[a]phenanthren-17-yl ester and is prepared using the
procedures described in WO 02/00679.

Example 1

[0067]An aerosol composition suitable for delivery from the canister of a
pressurised metered dose inhaler device is prepared by mixing the
ingredients listed in Table 1 below. Theophylline and Compound B are
milled to a mean particle diameter of 1-5 μm.

[0068]A dry powder suitable for delivery from the reservoir of the
multi-dose inhaler described in WO97/20589 is prepared by mixing the
ingredients listed in Table 1 below. Theophylline and Compound B are
milled to a mean particle diameter of 1-5 μm. The lactose monohydrate
has a particle diameter below 300 μm.

[0069]A dry powder suitable for delivery from the reservoir of the
multi-dose inhaler described in WO97/20589 is prepared by mixing 30 parts
of theophylline which has been milled to a mean particle diameter of 1-5
μm in an air-jet mill, 250 parts of Compound B which has been
similarly ground to a mean particle diameter of 1-5 μm and 4720 parts
of lactose monohydrate having a particle diameter below 300 μm.

Examples 4-92

[0070]Example 3 is repeated, but using the amounts of the ingredients
shown in Table 3 below in place of the amounts used in that Example:

[0071]Example 3 is repeated, but using the amounts of the ingredients
shown in Table 3 in place of the amounts used in that Example but also
containing 0.5% magnesium stearate by weight.

Examples 182-270

[0072]Example 3 is repeated, but using the amounts of the ingredients
shown in Table 3 in place of the amounts used in that Example but also
containing 1.0% magnesium stearate by weight.

Example 271

[0073]Gelatin capsules suitable for use in a capsule inhaler such as that
described in U.S. Pat. No. 3,991,761 are prepared, each capsule
containing a dry powder obtained by mixing 30 μg of theophylline which
has been milled to a mean particle diameter of 1 to 5 μm in an air jet
mill, 250 μg of Compound B which has been similarly milled to a mean
particle diameter of 1 to 5 μm and 24738 μg of lactose monohydrate
having a particle diameter below 300 μm.